Tumors Of Female Reproductive Organs Research Articles

Pten in mouse vagina.

It is well known that the phosphatase and tensin homolog deleted from chromosome 10 (Pten) is a tumor suppressor and is indispensable for epithelial cell homeostasis to prevent tumor formation. Mutations in Pten are frequently found both in sporadic and hereditary cancers, and mice with Pten deletion and/or loss-of-function mutations are highly susceptible to tumor induction by aberrant phosphatidylinositol 3-kinase (PI3K)/Akt pathway activation [1, 2]. The female reproductive tract (FRT) consists of the sites for reproduction and is of significant concern for women's health and disease, notably tumorigenesis. Despite the importance of this organ system, the molecular and cellular mechanisms that regulate cell proliferation and differentiation of these organs are not yet fully understood. Obviously, estrogen plays a central role in female reproductive organ biology. In the FRT, estrogen stimulation increases the organ weight, and promotes cell proliferation and differentiation, whereas estrogen withdrawal induces rapid involution, resulting in atrophy. These specific and reversible effects of estrogen are important in maintaining homeostasis and are required for normal health and reproduction. It is currently thought that excess estrogen stimulation plays a role in the etiology of hyperplasia and/or tumors in female reproductive organs. Therefore, homeostasis of FRT should be separately regulated according to the presence or absence of estrogen in order to prevent ectopic and excess cell proliferation, respectively. The mouse vagina exhibits a unique feature in response to estrogens and provides an intriguing model for analyzing stratified and squamous differentiation in the epithelium, because it undergoes characteristic changes from non-keratinized to a fully keratinized epithelium depending on the levels of endogenous estrogen during the estrous cycle. In addition, the mouse model allows a manipulation of estrogen levels by ovariectomy (OVX) and exogenous estrogen treatment. The vaginae of OVX mice show atrophied epithelia of 2-3 cell layers, whereas estrogen administration rapidly induces epithelial cell proliferation in the basal layer. The suprabasal cells are no longer mitogenic but differentiate while moving up through the epithelium. Finally, apical cells exhibit keratinization. The fully stratified and keratinized vaginal epithelium resembles the typical stratified and keratinized epidermis found in the skin and other organs. Pten has a pivotal role in maintaining stratified squamous epithelia, because conditional knockout (CKO) of Pten in the epithelium leads to hyperplasia, hyperkeratosis and tumor formation in squamous tissues (e.g., squamous cell carcinomas; SCC) [3]. In our current study [4], we utilized vaginal epithelium-specific conditional Pten knockout mice to elucidate the role of Pten in the vagina. PI3K/Akt signaling is a downstream and essential mediator for estrogen-induced events in FRT [5, 6]. We thus hypothesized that Akt activation by Pten mutation results in the phenocopy of estrogen-stimulated status and/or squamous epithelial hyperplasia even in the absence of estrogen. Pten CKO OVX mice, however, did not show such a simple phenotype, but exhibited epithelial hyperplasia in the suprabasal cells with increased cell mass and mucin production. No stratified epithelial cell markers, such as CK1 and filaggrin, were expressed. By contrast, estrogen administration to Pten CKO OVX mice induced stratification and keratinized differentiation in the vaginal epithelium as in the control mice. One of the most intriguing findings is that Pten is exclusively expressed in the suprabasal cells in the absence of estrogens, whereas estrogen administration induced Pten expression in the basal cells. Pten thus has dual roles in the vaginal epithelium, depending on the presence or absence of estrogen. In the absence of estrogen, Pten inhibits ectopic cell proliferation and abnormal mucin production in the suprabasal cells. In the presence of estrogen, Pten functions in the basal cells to prevent excessive basal cell proliferation as in the case of other squamous tissues. The current result that Pten regulates homeostasis of the vagina in different ways is quite unique and provides new insights into how Pten functions in tissue homeostasis. Primary vaginal cancer is rare, accounting for only 1-3% of gynecological malignancies, but SCC is the most common invasive malignancy of the cervix, vagina and vulva [7]. Our findings shed light on the underlying mechanisms of cancer biology associated with the Pten/PI3K/Akt signaling pathway and its crosstalk to estrogen.

Introduction of WHO classification of tumours of female reproductive organs, fourth edition

《WHO女性生殖器官肿瘤学分类(第4版)》[1](WHO Classification of Tumours of Female Reproductive Organs)终于出版了,距《WHO乳腺和女性生殖器官肿瘤病理学和遗传学分类》[2]的出版已经10年余.在此期间,女性生殖系统肿瘤病理领域出现了诸多进展,对一些疾病的认识有了进一步提高,同时对另一些疾病的性质、命名等仍存在许多争议.本书的出版期望对近十余年来妇科病理领域的学术进展进行了有效梳理,根据现有认识及循证医学证据,对有争议的问题进行了阶段性的厘清。

Erythropoietin is involved in growth and angiogenesis in malignant tumours of female reproductive organs.

The accumulating evidence that erythropoietin and erythropoietin receptor are expressed in various non-haematopoietic organs suggests that erythropoietin signalling might be involved in the growth of tumours, but this possibility has never been examined. We found that mRNAs for erythropoietin and erythropoietin receptor are expressed in malignant tumours of female reproductive organs, where erythropoietin levels are higher than in normal tissues. Furthermore, tumour cells and capillary endothelium showed erythropoietin receptor immunoreactivity. To investigate the role of the erythropoietin/erythropoietin receptor pathway in these tumours, we injected mouse monoclonal antibody against erythropoietin or the soluble form of erythropoietin receptor into blocks of tumour specimens and cultured the blocks. After 12 h of injections, these blocks were examined and compared with control blocks injected with mouse monoclonal antibody, heat denatured soluble form of erythropoietin receptor, mouse serum or saline. Tumour cells and capillaries were markedly decreased in a dose-dependent manner after either injection. A marked increase of the cells containing fragmented DNA and the histopathological characteristics of these cells suggest that the decrease in tumour cells and capillary endothelial cells was due to apoptotic cell death. The co-existence of JAK2 and phosphorylated-JAK2, and STAT5 and phosphorylated STAT5, all of which are involved in the mitogenic signalling of erythropoietin, was found frequently in tumour cells and capillary endothelial cells in the untreated blocks. In contrast, most of the phosphorylated-JAK2- or phosphorylated-STAT5-positive cells had disappeared in the experimental blocks. Moreover, reduced tyrosine phosphorylation of STAT5 in the experimental blocks was confirmed by western blotting analysis. The results strongly indicate that erythropoietin signalling contributes to the growth and/or survival of both transformed cells and capillary endothelial cells in these tumours. Thus, deprivation of erythropoietin signalling may be a useful therapy for erythropoietin-producing malignant tumours.

Estrogen receptor-mediated cross-talk with growth factor signaling pathways.

Estrogen (E2) palys critical roles in the development of tumors in female reproductive organs. Development of most breast cancers is dependent on E&sub2; in most cases. Most E&sub2; actions are considered to be exerted through two subtypes of Estrogen receptors (ERs), ERalpha and ERbeta. ERs belong to the nuclear receptor superfamily, and act as ligand-inducible transcription factors to activate transcription of a particular set of the target genes. Ligand-bound ER recruits at least two distinct classes of coactivator complexes. In estrogen-dependent breast cancer, growth factors are shown to often act synergisticaly with E&sub2;, and the breast cancer often become resistant to treatment of estogen antagonists. However, the molecular basis of this coupled regulation of growth factor and ER-mediated signaling and hormone-resistance are largely unknown. We have previously shown that MAP (mitogen-activated protein) kinase (MAPK) activated by growth factors phosphorylates and potentiates the N-terminal transactivation function (AF-1), indicating a possible molecular mechanism of a novel cross-talk between two signalings (Kato et al, 1995). Furthermore, we have identified a coactivator that specifically interacts with ER alpha AF-1 (Endoh et al, 1999). In this review, this cross-talk is discussed in terms of the transactivation function of ERs and their coactivators.

The role of radiotherapy in gynecology.

The program of radiotherapy in treating malignant tumors of female reproductive organs should be planned as a unit, considering administration of radium, x-ray, telecobalt, etc. Not only must the gynecologist understand the nature and action of radiation, but also the radiotherapist must have a thorough knowledge of the female organs. Careful examination must precede initiation of radiotherapy. The author presents a discussion of irradiation in various gynecologic diseases based on experience at the Radiumhemmet, Stockholm.